Review Article

Small Cell Lung Cancer: Where Do We Go From Here? Lauren Averett Byers, MD1 and Charles M. Rudin, MD, PhD2

Small cell lung cancer (SCLC) is an aggressive disease that accounts for approximately 14% of all lung cancers. In the United States, approximately 31,000 patients are diagnosed annually with SCLC. Despite numerous clinical trials, including at least 40 phase 3 trials since the 1970s, systemic treatment for patients with SCLC has not changed significantly in the past several decades. Consequently, the 5-year survival rate remains low at 75%-90% of SCLCs),4-6 results in an aggressive, highly complex disease at the molecular level with a large number of mutations present in each tumor.7,8 Lack of early detection methods

Compared with non–small cell lung cancers (NSCLC), SCLC is characterized by a rapid doubling time and early, widespread metastases. Consequently, most patients (60%-70%) will have extensive-stage (ES) disease at the time of diagnosis (defined as cancer that has spread beyond the ipsilateral lung and regional lymph nodes and cannot be included in a single radiation field). Recently, results from the National Lung Screening Trial highlighted the aggressive nature of SCLC and its propensity for characteristic early hematogenous spread.9,10 That study proved the value of screening high-risk patients with low-dose computed tomography (CT) imaging for the early detection of lung cancers overall. However, for patients who had SCLC identified (in contrast to those who had NSCLC), early detection did not reduce the number of patients who were diagnosed with ES disease, nor did it have an evident impact on survival for patients with SCLC. Specifically, 86% of the 125 patients who had SCLC identified through this early detection program had advanced disease at diagnosis. On the basis of these results, there are currently no methods with proven efficacy for the early detection of SCLC. Current treatment standards for limited-stage SCLC

The vigorous response of SCLC to frontline chemotherapy (roughly 60%-70% response rates11) and to radiation is starkly contrasted by its subsequent resistance to second-line and subsequent therapies after disease recurrence. In general, limited-stage (LS) SCLC (ie, cancer confined to the thorax in a single radiation field) is treated with concurrent chemoradiation, whereas ES-SCLC is treated with chemotherapy alone. The current state-of-the-art treatment for LS-SCLC has recently been reviewed in Cancer by Amini et al12 and typically includes cisplatin-etoposide chemotherapy in combination Corresponding author: Lauren Averett Byers, MD, The University of Texas MD Anderson Cancer Center 1515 Holcombe Boulevard, Unit 432, Houston, TX 7030; Fax: (713) 792-1220; [email protected] 1 Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas; 2Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland.

We thank Dr. Neda Kalhor for providing the cytology image of small cell lung cancer for Figure 2. DOI: 10.1002/cncr.29098, Received: July 23, 2014; Revised: August 29, 2014; Accepted: September 10, 2014, Published online Month 00, 2014 in Wiley Online Library (wileyonlinelibrary.com)

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with radiation therapy (RT). For LS-SCLC, clinical trials have established the superiority of hyperfractionated RT and the importance of beginning RT as early in the treatment course as possible (preferably during cycle 1 of chemotherapy).13-19 With these multimodality treatments, up to 20% of patients will have long-term disease control. However, a majority will recur despite definitive chemoradiation.20,21 Additional progress in the treatment of SCLC has included the use of prophylactic cranial irradiation in patients with ES-SCLC and LS-SCLC who have a response to their initial platinum-based chemotherapy.22,23 Current treatment standards for ES-SCLC

For patients with ES-SCLC, front-line treatment is platinum-based chemotherapy. Most patients in the United States receive platinum-etoposide (EP) chemotherapy (with either carboplatin or cisplatin), and some patients receive platinum-irinotecan as an alternative, especially outside the United States.24 After relapse, topotecan is the only second-line drug approved by the US Food and Drug Administration (FDA). However, despite its indication in this setting, topotecan has produced disappointing response rates. As with other second-line therapies, responses are typically higher in patients who experiences longer disease control after frontline, platinum-based therapy. For example, response rates may be as high as 25% in patients who relapse >3 months after the completion of EP, but the rates are only 3% to 6% if patients relapse 493 squamous carcinomas and 512 adenocarcinomas with molecular profiling to date).39-41 Unfortunately, similar efforts have not yet been possible in SCLC because of a lack of adequate tumor tissue (most patients are diagnosed with SCLC by fine-needle aspiration, and surgically resected specimens are relatively rare). Overview

To improve outcomes for patients with SCLC, therapies are needed that 1) improve the durability of responses to front-line therapy (including an increased number of patients with LS-SCLC who have long-term survival) and 2) have activity after disease relapse. To achieve this, we need to apply an approach similar to what has been done in NSCLC and other cancers, including in-depth characterization of potential drug targets and activated pathways present in SCLC, followed by translation of the most promising drug targets into the clinic. Furthermore, beyond profiling of treatment-naive tumors, there is an urgent need to better understand what drives therapeutic resistance in recurrent SCLC—because chemotherapy resistance to second-line and later treatments remains a key factor in poor patient outcomes. To make progress in these areas, there are several barriers specific to SCLC that must be addressed. These include, first and foremost, a lack of adequate tissue for molecular profiling. This is the result of rare surgical resections in SCLC, small diagnostic biopsies, and the absence of a validated biomarker (for treatment selection) Cancer

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that would necessitate more substantial diagnostic biopsies (and rebiopsies at the time of progression). Furthermore, given the rapid pace of disease progression, translation of new targets into the clinic will require multidisciplinary teams that can expedite biopsies and profiling to minimize the time to treatment initiation. In this review, we discuss the current state of SCLC treatment, established hallmarks of SCLC biology, existing challenges in translational research, and opportunities for progress. Recent Advances in SCLC Translational Research

Several recent advances in SCLC research have contributed to the understanding of SCLC biology, including the development of new animal models of SCLC to help facilitate translational studies.42-44 Some of these findings have led to the identification of new potential drug targets that are now being investigated in clinical trials. For example, among 127 interventional studies currently enrolling SCLC patients, novel drug targets under investigation include poly(ADP-ripose) polymerase 1 (PARP1), immune checkpoints, stem cell targets, and fibroblast growth factor receptor (FGFR).45 In addition, novel bioinformatics approaches have opened new avenues for exploring existing data, including the identification of existing drugs that potentially could be repurposed for SCLC treatment (eg, tricyclic antidepressants).46,47 Other investigators have recently demonstrated the potential of “liquid biopsies”—obtaining SCLC cells from a patient’s circulation that can be propagated in mouse models for subsequent molecular profiling and drug sensitivity screening.48 Molecular hallmarks of SCLC—and their clinical implications

The current classification system for lung cancers from the World Health Organization (WHO 2004) recognizes 3 high-grade lung cancers of neuroendocrine (NE) origin.49 These include SCLC, combined SCLC (which contain areas of NSCLC), and large cell NE cancer (LCNEC) (a subset of NSCLC). It is noteworthy that previous studies have demonstrated similarities at the protein and messenger RNA (mRNA) levels between SCLC and LCNEC, suggesting a related underlying biology.50-52 SCLC and other high-grade NE lung cancers are distinct in their biology and clinical behavior from intermediate-grade and low-grade NE cancers like atypical and typical carcinoid. SCLC is characterized by a nearly universal loss of tumor protein 53 (TP53) (75%-90% of patients)4-6 and 3

Review Article

Figure 1. The frequency of genomic alterations is illustrated according to percentage in small cell lung cancer (SCLC). This is a representative list of the more common and/or potentially targetable alterations. An asterisk indicates the percentage that was positive for poly(ADP-ripose) polymerase 1 (PARP1) protein expression based on the number of SCLC tumors that had an immunohistochemical staining score of 3 1 in 100% of tumor cells. TP53 indicates tumor protein 53; RB1, retinoblastoma 1; PTEN, phosphatase and tensin homolog; MYC, v-myc avian myelocytomatosis viral oncogene homolog; MYCL, v-myc avian myelocytomatosis viral oncogene lung carcinoma-derived homolog; MYCN, v-myc avian myelocytomatosis viral oncogene neuroblastoma-derived homolog; SOX2, sex-determining region Y box 2; FGFR1, fibroblast growth factor receptor 1; CCNE1, cyclin E1; EPHA7, ephrin receptor A7.

retinoblastoma 1 (RB1) (approaching 100%)53,54 and by frequent 3p deletion.55 Beyond these shared molecular features, increased expression of cKit,56,57 amplification v-myc avian myelocytomatosis viral oncogene homolog (MYC) family members (MYC, MYC lung carcinomaderived homolog 1 [MYCL1], and MYC neuroblastomaderived homolog [MYCN]),58 and loss of phosphatase and tensin homolog (PTEN) have also been described in subsets of SCLC. These molecular hallmarks of SCLC (or SCLC subsets) were confirmed in 2 recent comprehensive genomic profiling studies of SCLC.7,8 Consistent with prior studies, loss of the tumor suppressors TP53 and RB1 were the 2 most common events identified by both groups. However, those studies also identified novel mutations (eg, those in epigenetic regulators) and driver mutations with well established roles in multiple cancer types (eg, MYC family genes, BCL2, PTEN, CREB binding protein [CREBBP], and FGFR1) (Fig. 1). Myc alterations and targeting

Alterations in MYC family members were observed in approximately 20% of SCLC patient tumors. Unlike TP53 and RB1, which are tumor suppressors, MYC family members represent frequent oncogenes in SCLC and other cancer types. Although Myc has been recognized as a potentially important target for many years, designing a drug to directly inhibit Myc activity has been challenging. 4

However, MYC amplified or driven tumors may be more sensitive to certain emerging targeted drugs, such as Aurora kinase or bromodomain inhibitors.25,59,60 In 1 recent example, a phase 2 clinical trial of singleagent alisertib (a highly selective Aurora kinase A inhibitor) produced response rates of 21% in 47 patients with recurrent or progressive SCLC.61 Among these, the highest response rates were observed in patients with platinum-refractory SCLC (defined as disease recurrence within 3 months of completing front-line platinum-based therapy), typically the most drug-resistant population. Correlative studies from SCLC patients treated on this trial are pending; however, data from preclinical models of SCLC, as well as other cancer types, suggest that tumors with Myc alterations may be especially sensitive to Aurora kinase inhibitors.62,63 The mechanism through which MYC-amplified or Myc-overexpressing tumors are sensitized to inhibition of Aurora kinase is still incompletely understood. However, previous studies suggest that Myc plays an important role in transcriptional regulation of Aurora kinases A and B, which, in turn, may provide a growth advantage in the absence of p53.63-66 Because of the key role of Aurora kinase A in mitotic spindle assembly, these drugs may be especially active in combination with taxane chemotherapies. If the activity of Aurora kinase inhibitors is validated in subsequent SCLC clinical trials (such as a new study of paclitaxel with or without alisertib in second-line SCLC; National Clinical Trial no. NCT02038647), then Mycamplified SCLC could be the first genomically defined subgroup of SCLC with a specific targeted agent. In addition to the MYC amplifications mentioned above, others biomarkers and/or targets that may predict response in specific subsets of SCLC patients include those with mutations or amplification in FGFR159 or sexdetermining region Y box 2 (SOX2)8 and alterations affecting epigenetic changes, such as O-6-methylguanineDNA methyltransferase (MGMT) promoter methylation (associated with response to TMZ).26 Overexpression of PARP1 protein and potential role of DNA repair inhibitors

Beyond mutations and changes in DNA copy number, overexpression of certain proteins in SCLC tumors or changes at the epigenetic level may represent new and important therapeutic targets. For example, proteomic profiling of a large panel of SCLC cell lines led to the identification of several potentially novel therapeutic targets.52 These include the DNA repair proteins PARP1 and checkpoint kinase 1 (Chk1) as well as enhancer of Cancer

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zeste 2 polycomb repressive complex 2 subunit (EZH2) (a chromatin modulator). Increased expression of these proteins appears to be independent of alterations at the DNA level (mutation, amplification) in their corresponding genes (PARP1, CHEK1, and EZH2), emphasizing the value of comprehensive molecular profiling—ie, examining not just tumor DNA but alterations that occur at the protein or pathway level. On the basis of this observation, several PARP inhibitors (eg, olaparib, rucaparib, BMN-673) were then investigated in preclinical models of SCLC and exhibited single-agent activity in cell lines and/or animal models.52,67 Those results led to the investigation of PARP inhibitors (eg, BMN-673 and veliparib) in patients with SCLC in several clinical trials (eg, NCT01286987, NCT01642251, and NCT01638546). The first results of PARP inhibitors in SCLC patients were recently presented at the 2014 American Society of Clinical Oncology annual meeting and, among other findings, exhibited single-agent activity of the PARP inhibitor BMN-673 in a subset of SCLC patients.68 Other ongoing studies are testing the combination of PARP inhibition with chemotherapy and include a TMZ/veliparib combination for second-line or third-line treatment (NCT01638546) and a first-line trial of veliparib with platinum-etoposide (Eastern Cooperative Oncology Group trial ECOGE2511). Further studies are ongoing to identify biomarkers that may predict response to these drugs and include levels of PARP1 or other DNA repair proteins.67 Immunotherapy and other promising targets

Several immunotherapy approaches have been investigated or are under current investigation in SCLC, including vaccine studies, interferon-a, and several clinical trials of immune checkpoint inhibitors (for review, see Spigel and Socinski69). Immune checkpoint blockade, either alone or in combination with chemotherapy, represents a particularly promising approach to the treatment of this disease. For example, a randomized phase 2 study investigated the combination of ipilimumab (a monoclonal antibody targeting cytotoxic T-lymphocyte–associated antigen 4 [CTLA-4]) in combination with paclitaxel and carboplatin. One hundred thirty patients with treatmentnaive were randomized to 1 of 3 treatment arms: 1) concurrent ipilimumab (ipilimumab plus chemotherapy for 4 cycles followed by 2 cycles of chemotherapy plus placebo), 2) phased ipilimumab (chemotherapy plus placebo for 2 cycles followed by chemotherapy plus ipilimumab for 4 cycles), or 3) chemotherapy plus placebo. In the patients who received phased ipilimumab, an improvement was Cancer

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observed in progression-free survival based on immunerelated response criteria (hazard ratio, 0.64; P 5 .03), with a trend for improved overall survival (12.5 months vs 9.1 months).70 Several trials of immunotherapy in the first-line and relapsed settings are now ongoing, such as the investigation of a programmed cell death protein 1 (PD-1) inhibitor (nivolumab) combined with ipilimumab (NCT01928394). Another drug target with potential activity in SCLC is FGFR. Alterations (eg, amplification or mutation) in FGFR family members have been described in a small subset of SCLC tumors; and some, but not all, SCLC models with FGFR1 amplification have demonstrated sensitivity to FGFR inhibitors.59 Drugs targeting FGFR family members that are currently in clinical investigation for SCLC include JNJ-42756493 (a pan-FGFR inhibitor) and BIBF1120 (a multitargeted drug that inhibits FGFR, vascular endothelial growth factor receptor [VEGFR], and platelet-derived growth factor receptor [PDGFR]; NCT01703481 and NCT01441297). However, the extent to which SCLC with mutations and/or amplifications in FGFR family member genes are dependent on the FGFR pathway is not yet known. Current Barriers and Challenges in Translational SCLC Research

There are several barriers that have made translational research in SCLC particularly difficult. These include 1) limited tissue available for study, 2) the molecular complexity of SCLC, 3) a poor understanding of the mechanisms of chemotherapy resistance in recurrent disease (including unique molecular alterations that may be acquired after initial treatment), and 4) the rapid pace of disease progression. In addition, investment in SCLC research has been low in recent years (possibly because of some of the limitations noted above in contrast to NSCLC, in which research tools, including tissue and model systems, are more plentiful). For example, in fiscal Year 2012, the National Cancer Institute (NCI) research portfolio contained 745 projects that included lung cancer research, but only 17 (approximately 2%) of those had a focus on SCLC.71 Contribution of SCLC pathobiology to scarce tissue resources for research

SCLC cells are readily recognized by light microscopy because of their characteristic appearance as small blue cells, often with “crush” artifact (an effect of cell fixing). Thus, a diagnosis can be made based on the presence of as few as 3 to 10 cancer cells (Fig. 2). The ability to establish 5

Review Article

Figure 2. Tissue limitations in the study of small cell lung cancer are illustrated. NGS indicates next-generation DNA sequencing.

a diagnosis of SCLC from a small number of malignant cells, combined with infrequent surgical resection and a lack of validated predictive biomarkers that would necessitate larger tissue biopsies, has significantly limited the availability of SCLC tissue for molecular profiling and other scientific studies. This is especially true for profiling technologies which currently work best on frozen tissue in adequate quantities, including in-depth whole genome sequencing of DNA and comprehensive expression analysis for RNA and protein. To date, whole-exome sequencing data (ie, DNA sequencing of protein-coding regions of the genome) has only been published on 82 SCLC tumors.7,42 This is in stark contrast to NSCLC, for which data from more than 1000 NSCLC tumors have been published.9,35,39,41 This small number of profiled tumors is especially problematic in a disease like SCLC, which carries one of the highest rates of mutations per tumor42 because of long-term tobacco exposure and near universal loss of p53 function.4 On average, SCLC tumors have greater than 4 times the number of mutations observed in breast cancer and almost 10 times the number in prostate cancer.42 The vast majority of mutations observed in SCLC patient tumors are passengers (those that do not meaningfully contribute to disease behavior or progression). This makes it more difficult to definitively identify those mutations that are drivers of cancer growth and invasion (including those that may be druggable). The challenge of discriminating driver mutations from passengers is even more critical for cases in which a driver may only be present in a subset of SCLC patients. We know that driver genes—even those identified in only a minority of patients–still may have incredible clinical importance. For instance, although ALK fusions are identified in only 7% of lung adenocarcinomas, testing for ALK fusions has become a standard of care in the meta6

static setting, because we have highly effective, FDA-approved drugs targeting ALK (crizotinib and ceritinib) that provide substantial clinical benefit for a majority of ALK-positive patients.72-74 However, the genomic studies of SCLC to date have been insufficiently powered to reliably identify recurrent mutations present in 60 SCLC cell lines. Results from this drug screen and other ongoing preclinical efforts—combined with an integrated analysis of the molecular profiles of these SCLC cell lines75 (eg, mutations, amplifications, deletions, or alterations at the protein or pathway levels that correspond to drug sensitivity)—will provide important leads that can be validated in the laboratory and taken forward into clinical trials. As part of this, bioinformatics tools will allow us to mine these growing data sets for the new targets or biomarkers to maximize the value and use of a growing molecular resource/database in SCLC.47 Remarkably, only approximately 100 interventional clinical trials in SCLC have been registered at www.clinicaltrials.gov since December 2007. This number is clearly inadequate to meet the needs/demand that exists for SCLC patients—particularly with the goal of making a Cancer

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meaningful advance in patient outcomes in the short term. Critical clinical components of a successful SCLC translational research framework must also include 1) biopsy and rebiopsy programs to obtain adequate issue for molecular profiling, 2) mechanisms to support the logistics and funding of patient tumor profiling to identify potential drug targets (such as cooperative group programs or other laboratory protocols), and 3) clinical trial options for all stages of disease that meet the needs of our patients and respond to emerging discoveries/targets identified by ongoing profiling efforts or other research (eg, clinical trial consortiums, basket studies, SCLC master protocols). Figure 3 is an illustration of the key elements to a successful translational approach for the advancement of SCLC treatment, in which CLIA-approved biomarker testing to guide therapeutic selection is occurring in parallel to potentially transformative exploratory analyses. Furthermore, beyond SCLC of the lung, there is a similarly underserved group of patients with extrapulmonary small cell carcinoma. Partnerships of pulmonary and extrapulmonary small cell efforts also potentially could advance our understanding of SCLC biology and opportunities for clinical trials of shared targets. Although the aggressiveness of SCLC introduces challenges to clinical research (such as the need for efficient decision making, biopsy completion, and initiation of therapy), previous studies, such as the Biomarker-Integrated Approaches of Targeted Therapy for Lung Cancer Elimination 1 (BATTLE1) trial and, more recently, the BATTLE2 trial (both for metastatic, relapsed NSCLC), have demonstrated the feasibility of obtaining fresh biopsies in a population of patients with advanced, chemotherapy-resistant disease.76 Summary

SCLC is an aggressive disease affecting >30,000 individuals per year in the United States. Most patients present with advanced disease and rapidly develop treatment resistance despite a high rate of responses to initial chemotherapy and radiation. Regardless of numerous clinical trials, treatment has not changed significantly for more than 30 years. Progress in the treatment of SCLC has been limited by several factors, including limited tissue availability for translational research. Consequently, SCLC lags significantly behind NSCLC and other cancers in molecular profiling and the development of targeted therapies. Despite these challenges, there have been some notable recent discoveries that have led to clinical trials and have the potential to advance the field. By using a multidisciplinary, collaborative, crossinstitutional approach, we have the opportunity to 7

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meaningfully impact outcomes in the next 5 to 10 years. Important steps toward this goal will include a coordinated effort to collect adequate SCLC tumor tissue for research from treatment-naive and treatment-refractory patients, support for a scientific community of SCLC investigators, and a framework for translating the most promising discoveries into clinical trials and, ultimately, clinical practice. FUNDING SUPPORT L.B. is supported, in part, by the R. Lee Clark Fellow Award (supported by the Jeane F. Shelby Scholarship Fund), the MDACC Physician Scientist Award, and the NCI Cancer Clinical Investigator Team Leadership Award.

CONFLICT OF INTEREST DISCLOSURES Dr. Byers reports consulting fees from BioMarin and AbbVie outside the submitted work. Dr. Rudin reports consulting fees from AbbVie, Aveo/Biodesik, Boehringer Ingelheim, GlaxoSmithKline, and Merck outside the submitted work.

REFERENCES 1. American Cancer Society. Cancer Facts & Figures 2014. Atlanta, GA: American Cancer Society; 2014. 2. Varghese AM, Zakowski MF, Yu HA, et al. Small-cell lung cancers in patients who never smoked cigarettes. J Thorac Oncol. 2014;9: 892-896. 3. Ettinger DS, Aisner J. Changing face of small-cell lung cancer: real and artifact. J Clin Oncol. 2006;24:4526-4527. 4. Miller CW, Simon K, Aslo A, et al. p53 mutations in human lung tumors. Cancer Res. 1992;52:1695-1698. 5. Takahashi T, Suzuki H, Hida T, Sekido Y, Ariyoshi Y, Ueda R. The p53 gene is very frequently mutated in small-cell lung cancer with a distinct nucleotide substitution pattern. Oncogene. 1991;6: 1775-1778. 6. D’Amico D, Carbone D, Mitsudomi T, et al. High frequency of somatically acquired p53 mutations in small-cell lung cancer cell lines and tumors. Oncogene. 1992;7:339-346. 7. Peifer M, Fernandez-Cuesta L, Sos ML, et al. Integrative genome analyses identify key somatic driver mutations of small-cell lung cancer. Nat Genet. 2012;44:1104-1110. 8. Rudin CM, Durinck S, Stawiski EW, et al. Comprehensive genomic analysis identifies SOX2 as a frequently amplified gene in small-cell lung cancer. Nat Genet. 2012;44:1111-1116. 9. Aberle DR, DeMello S, Berg CD, et al. Results of the 2 incidence screenings in the National Lung Screening Trial. N Engl J Med. 2013;369:920-931. 10. Aberle DR, Adams AM, Berg CD, et al. Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med. 2011;365:395-409. 11. Simon M, Argiris A, Murren JR. Progress in the therapy of small cell lung cancer. Crit Rev Oncol Hematol. 2004;49:119-133. 12. Amini A, Byers LA, Welsh JW, Komaki RU. Progress in the management of limited-stage small cell lung cancer. Cancer. 2014;120: 790-798. 13. Spiro SG, James LE, Rudd RM, et al. Early compared with late radiotherapy in combined modality treatment for limited disease small-cell lung cancer: a London Lung Cancer Group multicenter randomized clinical trial and meta-analysis. J Clin Oncol. 2006;24: 3823-3830. 14. Fried DB, Morris DE, Poole C, et al. Systematic review evaluating the timing of thoracic radiation therapy in combined modality therapy for limited-stage small-cell lung cancer. J Clin Oncol. 2004;22: 4837-4845.

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15. De Ruysscher D, Pijls-Johannesma M, Bentzen SM, et al. Time between the first day of chemotherapy and the last day of chest radiation is the most important predictor of survival in limited-disease small-cell lung cancer. J Clin Oncol. 2006;24:1057-1063. 16. Pijls-Johannesma MC, De Ruysscher D, Lambin P, Rutten I, Vansteenkiste JF. Early versus late chest radiotherapy for limited stage small cell lung cancer [serial online]. Cochrane Database Syst Rev. 2005;(1):CD004700. 17. De Ruysscher D, Pijls-Johannesma M, Vansteenkiste J, Kester A, Rutten I, Lambin P. Systematic review and meta-analysis of randomised, controlled trials of the timing of chest radiotherapy in patients with limited-stage, small-cell lung cancer. Ann Oncol. 2006; 17:543-552. 18. Huncharek M, McGarry R. A meta-analysis of the timing of chest irradiation in the combined modality treatment of limited-stage small cell lung cancer. Oncologist. 2004;9:665-672. 19. Turrisi AT 3rd, Kim K, Blum R, et al. Twice-daily compared with once-daily thoracic radiotherapy in limited small-cell lung cancer treated concurrently with cisplatin and etoposide. N Engl J Med. 1999;340:265-271. 20. Demedts IK, Vermaelen KY, van Meerbeeck JP. Treatment of extensive-stage small cell lung carcinoma: current status and future prospects. Eur Respir J. 2010;35:202-215. 21. Johnson BE, Janne PA. Basic treatment considerations using chemotherapy for patients with small cell lung cancer. Hematol Oncol Clin North Am. 2004;18:309-322. 22. Auperin A, Arriagada R, Pignon JP, et al. Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission. Prophylactic Cranial Irradiation Overview Collaborative Group. N Engl J Med. 1999;341:476-484. 23. Slotman B, Faivre-Finn C, Kramer G, et al. Prophylactic cranial irradiation in extensive small-cell lung cancer. N Engl J Med. 2007; 357:664-672. 24. National Comprehensive Cancer Network. Small cell lung cancer. Available at: http://www.nccn.org/professionals/physician_gls/pdf/ sclc.pdf. Accessed July 18, 2014. 25. Simos D, Sajjady G, Sergi M, et al. Third-line chemotherapy in small-cell lung cancer: an international analysis. Clin Lung Cancer. 2014;15:110-118. 26. Pietanza MC, Kadota K, Huberman K, et al. Phase II trial of temozolomide in patients with relapsed sensitive or refractory small cell lung cancer, with assessment of methylguanine-DNA methyltransferase as a potential biomarker. Clin Cancer Res. 2012;18:1138-1145. 27. Lara PN Jr, Natale R, Crowley J, et al. Phase III trial of irinotecan/ cisplatin compared with etoposide/cisplatin in extensive-stage smallcell lung cancer: clinical and pharmacogenomic results from SWOG S0124. J Clin Oncol. 2009;27:2530-2535. 28. Noda K, Nishiwaki Y, Kawahara M, et al. Irinotecan plus cisplatin compared with etoposide plus cisplatin for extensive small-cell lung cancer. N Engl J Med. 2002;346:85-91. 29. Zatloukal P, Cardenal F, Szczesna A, et al. A multicenter international randomized phase III study comparing cisplatin in combination with irinotecan or etoposide in previously untreated small-cell lung cancer patients with extensive disease. Ann Oncol. 2010;21: 1810-1816. 30. Hanna N, Bunn PA Jr, Langer C, et al. Randomized phase III trial comparing irinotecan/cisplatin with etoposide/cisplatin in patients with previously untreated extensive-stage disease small-cell lung cancer. J Clin Oncol. 2006;24:2038-2043. 31. Socinski MA, Smit EF, Lorigan P, et al. Phase III study of pemetrexed plus carboplatin compared with etoposide plus carboplatin in chemotherapy-naive patients with extensive-stage small-cell lung cancer. J Clin Oncol. 2009;27:4787-4792. 32. Rudin CM, Salgia R, Wang X, et al. Randomized phase II study of carboplatin and etoposide with or without the bcl-2 antisense oligonucleotide oblimersen for extensive-stage small-cell lung cancer: CALGB 30103. J Clin Oncol. 2008;26:870-876. 33. Dy GK, Miller AA, Mandrekar SJ, et al. A phase II trial of imatinib (ST1571) in patients with c-kit expressing relapsed small-cell lung cancer: a CALGB and NCCTG study. Ann Oncol. 2005;16:18111186.

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SCLC: Where Do We Go From Here?/Byers and Rudin

34. Krug LM, Crapanzano JP, Azzoli CG, et al. Imatinib mesylate lacks activity in small cell lung carcinoma expressing c-kit protein: a phase II clinical trial. Cancer. 2005;103:2128-2131. 35. Oze I, Hotta K, Kiura K, et al. Twenty-seven years of phase III trials for patients with extensive disease small-cell lung cancer: disappointing results [serial online]. PLoS One. 2009;4:e7835. 36. Chute JP, Chen T, Feigal E, Simon R, Johnson BE. Twenty years of phase III trials for patients with extensive-stage small-cell lung cancer: perceptible progress. J Clin Oncol. 1999;17:1794-1801. 37. National Comprehensive Cancer Network. NCCN guidelines: nonsmall cell lung cancer. Available at: http://www.nccn.org/professionals/physician_gls/f_guidelines.asp#nscl. Accessed July 18, 2014. 38. My Cancer Genome. Available at: http://www.mycancergenome.org/. Accessed July 18, 2014. 39. The Cancer Genome Atlas Research Network. Comprehensive molecular profiling of lung adenocarcinoma. Nature. 2014;511:543550. 40. National Cancer Institute, National Human Genome Research Institute. The Cancer Genome Atlas (TCGA) Research Network. Available at: http://cancergenome.nih.gov/. Accessed July 18, 2014. 41. Cancer Genome Atlas Research Network. Comprehensive genomic characterization of squamous cell lung cancers. Nature. 2012;489: 519-525. 42. Daniel VC, Marchionni L, Hierman JS, et al. A primary xenograft model of small-cell lung cancer reveals irreversible changes in gene expression imposed by culture in vitro. Cancer Res. 2009;69:33643373. 43. Meuwissen R, Linn SC, Linnoila RI, Zevenhoven J, Mooi WJ, Berns A. Induction of small cell lung cancer by somatic inactivation of both Trp53 and Rb1 in a conditional mouse model. Cancer Cell. 2003;4:181-189. 44. Schaffer BE, Park KS, Yiu G, et al. Loss of p130 accelerates tumor development in a mouse model for human small-cell lung carcinoma. Cancer Res. 2010;70:3877-3883. 45. National Institutes of Health. ClinicalTrials.gov. Available at: www.clinicaltrials.gov. Accessed July 18, 2014. 46. Jahchan NS, Dudley JT, Mazur PK, et al. A drug repositioning approach identifies tricyclic antidepressants as inhibitors of small cell lung cancer and other neuroendocrine tumors. Cancer Discov. 2013; 3:1364-1377. 47. Wang J, Byers LA. Teaching an old dog new tricks: drug repositioning in small cell lung cancer. Cancer Discov. 2013;3:1333-1335. 48. Hodgkinson CL, Morrow CJ, Li Y, et al. Tumorigenicity and genetic profiling of circulating tumor cells in small-cell lung cancer. Nat Med. 2014;20:897-903. 49. Hirsch FR, Matthews MJ, Aisner S, et al. Histopathologic classification of small cell lung cancer. Changing concepts and terminology. Cancer. 1988;62:973-977. 50. Jones MH, Virtanen C, Honjoh D, et al. Two prognostically significant subtypes of high-grade lung neuroendocrine tumours independent of small-cell and large-cell neuroendocrine carcinomas identified by gene expression profiles. Lancet. 2004;363:775-781. 51. Peng WX, Shibata T, Katoh H, et al. Array-based comparative genomic hybridization analysis of high-grade neuroendocrine tumors of the lung. Cancer Sci. 2005;96:661-667. 52. Byers LA, Wang J, Nilsson MB, et al. Proteomic profiling identifies dysregulated pathways in small cell lung cancer and novel therapeutic targets including PARP1. Cancer Discov. 2012;2:798-811. 53. Helin K, Holm K, Niebuhr A, et al. Loss of the retinoblastoma protein-related p130 protein in small cell lung carcinoma. Proc Natl Acad Sci U S A. 1997;94:6933-6938. 54. Kaye FJ. RB and cyclin dependent kinase pathways: defining a distinction between RB and p16 loss in lung cancer. Oncogene. 2002; 21:6908-6914. 55. Wistuba II, Behrens C, Virmani AK, et al. High resolution chromosome 3p allelotyping of human lung cancer and preneoplastic/preinvasive bronchial epithelium reveals multiple, discontinuous sites of 3p allele loss and 3 regions of frequent breakpoints. Cancer Res. 2000;60:1949-1960.

Cancer

Month 00, 2014

56. Rohr UP, Rehfeld N, Pflugfelder L, et al. Expression of the tyrosine kinase c-kit is an independent prognostic factor in patients with small cell lung cancer. Int J Cancer. 2004;111:259-263. 57. Tamborini E, Bonadiman L, Negri T, et al. Detection of overexpressed and phosphorylated wild-type kit receptor in surgical specimens of small cell lung cancer. Clinical Cancer Res. 2004;10:82148219. 58. Wistuba II, Gazdar AF, Minna JD. Molecular genetics of small cell lung carcinoma. Semin Oncol. 2001;28(2 suppl):3-13. 59. Sos ML, Dietlein F, Peifer M, et al. A framework for identification of actionable cancer genome dependencies in small cell lung cancer. Proc Natl Acad Sci U S A. 2012;109:17034-17039. 60. Mertz JA, Conery AR, Bryant BM, et al. Targeting MYC dependence in cancer by inhibiting BET bromodomains. Proc Natl Acad Sci U S A. 2011;108:16669-16674. 61. Melichar B, Adenis A, Havel L, et al. Phase (Ph) I/II study of investigational Aurora A kinase (AAK) inhibitor MLN8237 (alisertib): updated ph II results in patients (pts) with small cell lung cancer (SCLC), non-SCLC (NSCLC), breast cancer (BrC), head and neck squamous cell carcinoma (HNSCC), and gastroesophageal cancer (GE) [abstract]. J Clin Oncol. 2014;31(suppl). Abstract 605. 62. Hook KE, Garza SJ, Lira ME, et al. An integrated genomic approach to identify predictive biomarkers of response to the aurora kinase inhibitor PF-03814735. Mol Cancer Ther. 2012;11:710-719. 63. Brockmann M, Poon E, Berry T, et al. Small molecule inhibitors of aurora-a induce proteasomal degradation of N-myc in childhood neuroblastoma. Cancer Cell. 2013;24:75-89. 64. den Hollander J, Rimpi S, Doherty JR, et al. Aurora kinases A and B are up-regulated by Myc and are essential for maintenance of the malignant state. Blood. 2010;116:1498-1505. 65. Lu LY, Wood JL, Ye L, et al. Aurora A is essential for early embryonic development and tumor suppression. J Biol Chem. 2008;283: 31785-31790. 66. Vader G, Lens SM. The Aurora kinase family in cell division and cancer. Biochim Biophys Acta. 2008;1786:60-72. 67. Cardnell RJ, Feng Y, Diao L, et al. Proteomic markers of DNA repair and PI3K pathway activation predict response to the PARP inhibitor BMN 673 in small cell lung cancer. Clin Cancer Res. 2013; 19:6322-6328. 68. Wainberg Z, Rafii S, Ramanathan R, et al. Safety and antitumor activity of the PARP inhibitor BMN673 in a phase 1 trial recruiting metastatic small-cell lung cancer (SCLC) and germline BRCAmutation carrier cancer patients [abstract]. J Clin Oncol. 2014; 32(5s). Abstract 7522. 69. Spigel DR, Socinski MA. Rationale for chemotherapy, immunotherapy, and checkpoint blockade in SCLC: beyond traditional treatment approaches. J Thorac Oncol. 2013;8:587-598. 70. Reck M, Bondarenko I, Luft A, et al. Ipilimumab in combination with paclitaxel and carboplatin as first-line therapy in extensivedisease-small-cell lung cancer: results from a randomized, doubleblind, multicenter phase 2 trial. Ann Oncol. 2013;24:75-83. 71. National Cancer Institute. Group Scientific Framework for Small Cell Lung Cancer (SCLC). Bethesda, MD: National Cancer Institute, Small Cell Lung Cancer Working Group; 2014. 72. Shaw AT, Kim DW, Mehra R, et al. Ceritinib in ALK-rearranged non-small-cell lung cancer. N Engl J Med. 2014;370:1189-1197. 73. Shaw AT, Kim DW, Nakagawa K, et al. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med. 2013; 368:2385-2394. 74. Mok T Kim DW, Wu YL, et al. First-line crizotinib versus pemetrexed-cisplatin or pemetrexed-carboplatin in patients (pts) with advanced ALK-positive non-squamous non-small cell lung cancer (NSCLC): results of a phase III study (PROFILE 1014) [abstract]. J Clin Oncol. 2014;32(5s). Abstract 8002. 75. Teicher BA. Perspective: opportunities in recalcitrant, rare and neglected tumors. Oncol Rep. 2013;30:1030-1034. 76. Kim ES, Herbst RS, Wistuba II, et al. The BATTLE trial: personalizing therapy for lung cancer. Cancer Dis. 2011;1:44-53.

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Small cell lung cancer: where do we go from here?

Small cell lung cancer (SCLC) is an aggressive disease that accounts for approximately 14% of all lung cancers. In the United States, approximately 31...
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